This grant proposal is in response to PAR-98-087, and is linked to K08-DK02603, which focuses on the role of Nrf1 in oxidative stress. The CNC family of transcription factors consists of several closely related members (p45NFE2, Nrf1, Nrf2 and Nrf3) that interact with the same regulatory DNA sequences. While CNC factors were isolated from globin gene expression studies, knockout experiments in mice failed to show a role for these factors in globin expression. Recent studies by our group and others provide evidence to suggest the importance of CNC transcription factors, Nrf1 and Nrf2, in the oxidative-stress response. One of our long-term goals is to understand the roles of these factors in the oxidative stress response in intact mouse models. Because conventional gene targeting of the nrf1 gene results in embryonic lethality, the analysis of Nrf1 in the oxidative stress response pathway beyond embryonic life is not possible. Thus, the goal of this two-year project is to develop a conditional gene targeting strategy based on the Cre-loxP system to generate mice in which temporal- and tissue-specific ablation of the Nrf1 function can be accomplished. Such a mouse will allow the study of Nrf1 function in the oxidative stress response in specific tissues where Nrf1 is highly expressed in adult mice. The use of conditional knockout models will not only provide basic information regarding the regulation of oxidative stress response by Nrf1, but also potentially provide strains of oxidant-sensitive mice that can be used to monitor environmental toxins in various tissue compartments.